Note that the following discussion refers to a number of publications and references. Discussion of such publications herein is given for more complete background of the scientific principles and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Many adverse health conditions result in the accumulation of abnormal compositions in the blood. For example, excess drugs given to patients, self consumed drugs and alcohol, and other consumables may be reflected in abnormal blood compositions. Some of the components found in the blood of affected individuals are used as diagnostic markers for disease and health conditions, while others may contribute to further problems by causing secondary symptoms and conditions. Medical treatment in such cases aim at reducing, masking or counteracting the effects of specific molecules and toxins, and supporting body processes that facilitate their clearance from the body. When symptoms become severe, the body can no longer handle the abnormal compositions, and facilitated medical intervention may be insufficient. Patients may suffer permanent damage or even death as a result.
Aphaeresis is a well-established clinical method that is used to separate components of blood for treatment or donation. In this method components of the blood which span a relatively narrow range of densities, but a much wider range of molecular weight and size, can be efficiently, rapidly, and continuously separated. Because blood is a heterogeneous non-ideal fluid, and most of the molecules and/or cells that are diagnostic for a disease fall within the density range spanned by the largest and smallest blood components, conventional aphaeresis is often ineffective or inefficient as an exclusive therapeutic device to collect and reduce the body's disease load, except possibly in cases where a major blood component is exchanged for a similar component obtained from healthy individuals (e.g. transfusion of red blood cells, harvesting of stem cells, platelets, white cells, removal of defective cells, etc.). Even some cells like metastatic cancer cells and stem cells are similar enough to normally present blood corpuscles to make separation difficult. Separation by aphaeresis is based on density and many undesirable components cannot be separated by density.
There are many situations where separation of targets from fluids is desirable. For example, patients with malignant cancer are typically treated with radiation and chemotherapeutic agents by scheduled infusion. Despite these efforts for many cancers the frequency of recurrence and metastasis remains significant. In some cases the cancer may be kept at bay if evidence for recurrence or continued malignancy could be caught early and the therapy modified appropriately. However, detecting evidence for metastatic cancer cells at early stages is difficult. By the time imaging and blood chemistry markers are able to reveal a problem the metastatic cancer is advanced and more aggressive treatment is required. Exacerbating this problem is the potential for some cancer cells to change their resistance to drug over time, which suggests that if effective detection and eradication could occur at early stages then patient prognosis could be significantly improved. Moreover, when present in sufficient quantity, certain cancer cells can be isolated from tissues such as blood and detected using immunological methods. Diagnosis therefore relies on the ability to find these diseased cells, which may be present in exceedingly small quantities.
Treatments of some viral diseases are available and preventable by immunization, but others are not. A patient who has not been immunized for a viral disease may be able to develop natural immunity and eventually build resistance to the disease. During this period, however, the patient may suffer from fever, infection and even life threatening symptoms, despite the intervention of indirect treatments to ease symptoms. Thus, being able to directly reduce the proliferation of viruses in the body of patients in crisis situations could bring significant benefits leading to recovery from viral diseases. In addition, it has become evident that methods to remove viruses (e.g., HIV, Ebola, or Hepatitis C) early in the infection greatly impacts prognosis and the effect of therapeutic treatments. Similarly, studies have shown that reducing the initial exposure load to toxins (e.g. snake bites, bacterial, or insect bites) can dramatically affect recovery, even avert death. Whether or not anti-toxin is available, by reducing the initial toxin load by removing toxins from the blood, neurotoxic, hemotoxic, necrotic, and other damage, as well as time spent in the hospital, may be minimized and disfigurement and death prevented.
Chelation therapeutics are drugs that are taken by patients exhibiting signs of excessively high metal levels such as iron. Taken by injection or orally these drugs supplement the transfusion therapy and prolong patient well-being and avoid crisis. Compliance with injection regimes has been difficult, but greatly improved with new oral medications. Bioavailability of oral drugs is still problematic and side effects arising from the larger than needed dosages that must be taken to reach consistent therapeutic levels is still an issue. The ability to lower iron levels in the blood could reduce side effects of transfusion therapy as well as alleviate the suffering of those with excess iron in the blood.
Patients with chronic hemoglobinopathies and other hemolytic diseases are typically treated by regular transfusion to replace lost oxygen carrying function and remove defective cells and their breakdown products. However, unlike the blood cells normally produced in the body, transfused blood cells are more fragile and tend to break down quicker in the blood stream. This leads to release of free iron from hemoglobin into the blood and eventual accumulation of iron in tissues and organs since the normal transferrin/ferritin network becomes overloaded and clearance of iron from the body cannot keep up. In those individual with defective iron clearance systems such as those with iron overload syndrome, the problem is even more acute.
In case of sickle cell anemia, the red blood cells (RBC) of patients are hemolyzed and the hemoglobin (HbS) released in the plasma become a cause of severe oxidative stress. Specifically, intravascular release of the tetrameric Hb results in its disassociation into a dimeric form. As a reactive molecule, hemoglobin can generate oxidant species. Outside a red blood cell, hemoglobin can react with plasma compounds, leading to oxidations. Free hemoglobin (Hb) is linked to the susceptibility of deoxyhemoglobin to oxidation, leading to the production of methemoglobin, which has a peroxidative activity and forms further reactive O2 species. Oxidation of methemoglobin also releases hemin, which rapidly associates with membranes, leading to cytotoxicity. The Hb scavenger Haptoglobin (Hp) will irreversibly bind the dimeric form of Hb. The Hp-Hb complex can associate with the receptor CD163, found on the surface of monocytes and macrophages and then endocytosed for removal by degradation in the liver. However, when the binding capacity of Hp is overwhelmed, the hemoglobin (Hb) can reach and overload the absorptive capacity of the kidney (hemoglobinuria), leading to nephrotoxicity. Plasma free hemoglobin (PFH) is one of the causes of serious oxidative side effects in patients with sickle cell anemia (SCA). The PFH circulating in the blood damages the patient's tissues and organs.
Treatment of these diseases mostly relies on drugs, high energy radiation, temperature, immunity, etc., which usually take place while these pathogens still reside in the body of the patient, which causes unwanted side effects. Thus there is a need for a therapeutic method that removes those pathogens/unwanted molecules from the blood circulation of the patient.
Use of retrievable nanoparticles (rNP) functionalized with a capture molecule (rNP-capture molecule) capable of binding to a target of interest if present in solution is useful for removing molecules of interest from fluid especially biological fluid. Mechanical mixing of the solution containing the rNP-capture molecule and its target of interest decreases the segregation of the rNP-capture molecule and its target in solution and enhances the rate of binding of the rNP-capture molecule and target of interest by increasing the rate of random collision. Common mechanical mixing techniques to decrease segregation of molecules in solution include vortexing, tilt mixing, stirring with paddle or magnet, shaking solution with a shaker plate, and inversion mixing for example to induce turbulence. Turbulence may randomly increase the collision frequency between nanoparticles and molecules.